Download Regulation of gene expression by polyunsaturated fatty acids

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Regulation of gene expression by
polyunsaturated fatty acids
Harini Sampath and James M. Ntambi
Departments of Nutritional Sciences and Biochemistry, University of Wisconsin,
Madison, Wisconsin, USA
Correspondence: James M. Ntambi, Department of Biochemistry, University of Wisconsin,
433 Babcock Drive, Madison, WI, 53706, USA.
Tel: +1 608 265 3700; fax: +1 608 265 3272; e-mail: [email protected]
Abstract
Consumption of polyunsaturated fatty acids (PUFAs) has been shown to be beneficial in the prevention
of several human diseases, including obesity, diabetes, heart disease, and stroke. It has become clear that
linolenic (n-3) and linoleic (n-6) PUFAs can act at the nuclear level to affect expression of genes involved
in diverse metabolic pathways. PUFAs act via nuclear receptors such as peroxisome proliferator
activated receptor a and liver X receptor a, and through the transcription factor, sterol regulatory
element binding protein-1c, to elicit a favorable hypolipidemic phenotype. Further understanding of the
molecular effects of PUFAs will be key to devising novel approaches to the treatment and prevention of
disease.
Heart Metab. 2006;32:32–35.
Keywords: Polyunsaturated fatty acids, SREBP1c, PPARa, LXRa
Introduction
Linoleic (n-6) and linolenic (n-3) acids are polyunsaturated fatty acids (PUFAs) that cannot be synthesized
de novo by mammals and are hence considered to be
essential to the diet. n-3 (or omega-3) PUFAs, including eicosapentaenoic acid and docosahexanoic acid,
are concentrated in marine mammals and high-fat
fish, whereas the main sources of dietary n-6 PUFAs
are vegetable oils and organ meats. n-3 PUFAs have
been shown to promote fatty acid oxidation while
decreasing the rates of lipid synthesis [1]. They have
also been shown to decrease plasma lipid concentrations [2] and enhance insulin sensitivity [3]. In
addition, they are believed to be preventive in various
chronic diseases, including rheumatoid arthritis [4],
coronary heart disease [5], and stroke [6], and certain
types of cancer, including breast, prostate, and colorectal cancers [7,8]. These beneficial effects of PUFAs
This work was supported by American Heart Association Predoctoral fellowship 0415001Z (Harini Sampath) and NIH grant NIDDKR0162388 (James M. Ntambi).
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are of obvious therapeutic interest; however, there
has also been some concern over excess consumption
of n-6 PUFAs, because of their proinflammatory and
proaggregatory effects [9]. Thus understanding the
mechanisms by which these fatty acids exert their
effects will be key to understanding whether and how
PUFAs can help promote optimal health and in
establishing a much-needed healthy dietary n-3 :
n-6 ratio.
Regulation of genes by polyunsaturated fatty
acids
Once fatty acids enter the cell, they are rapidly converted to fatty acyl coenzyme A (CoA) thioesters by an
acyl CoA synthetase [10] (Figure 1). This reaction is
essential to the further partitioning of fatty acids into
various pathways, including complex lipid synthesis,
b-oxidation, elongation/desaturation, and production of secondary signaling intermediates such as
prostaglandins, thromboxanes, and leukotrienes
Heart Metab. 2006; 32:32–35
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Regulation of gene expression by PUFAs
Figure 1. Regulation of gene expression by fatty acids and their metabolites. Non esterified fatty acids (NEFA) are transported
into the cell (1) and are rapidly converted to acyl coenzyme A (CoA) by acyl CoA synthetase (ACS) (2). The acyl CoA can
be oxidized (3) or can be esterified into complex lipids (4) such as triglycerides (TG), phospholipids (PL), or diacylglycerols
(DAG). These complex lipids can also replenish the cellular fatty acid stores as necessary (5). Alternatively, fatty acyl CoAs
can give rise to leukotrienes, prostaglandins, and thromboxanes (6). These secondary metabolites, in addition to complex
lipids such as DAG, can increase cellular concentrations of second messengers such as cyclic AMP (cAMP), inositol
triphosphate (IP3), and calcium (Ca) (7). These second messengers or their lipid precursors can all have effects on gene
expression (8). Alternatively, free fatty acids and fatty acyl CoAs can act directly at the nuclear level (9). In the nucleus,
signaling through fatty acids or their metabolites can lead to changes in nuclear receptor activation (10), as in the case of
peroxisome proliferator activated receptors and liver X receptors, or to changes in transcription factor abundance (11), as in
the case of sterol regulatory element binding protein-1c, leading to upregulation (12) or downregulation (13) of target genes.
DBD, DNA binding domain; LBD, ligand binding domain.
(Figure 1), which can in turn lead to changes in
production of cellular second messengers such as
inositol triphosphate, cyclic AMP (cAMP) and calcium
(Figure 1). Because of the rapid nature of the acyl CoA
synthetase reaction and the several fates of cellular
fatty acids, the free fatty acid concentration within the
cell is generally maintained at very low values. Thus
the molecular effects of fatty acids within cells are
likely to be mediated, not only by free fatty acids,
but also by fatty acyl CoAs and second messengers
(Figure 1).
It is now clear that PUFAs do not regulate gene
expression exclusively through changes in membrane composition or through production of secondary signaling intermediates. The discovery by
Gottlicher et al [11] of a nuclear receptor capable
of binding fatty acids established a direct role for
PUFAs in gene regulation. PUFAs have been shown
to exert their effects on gene transcription very rapidly
[12]. Within hours of animals being fed diets rich in
Heart Metab. 2006; 32:32–35
PUFAs, there is coordinated induction of expression
of genes involved in hepatic and skeletal muscle fatty
acid oxidation, and repression of genes that encode
lipogenic, glycolytic, and cholesterolgenic enzymes
[12]. This dual action results in a hypolipidemic
phenotype [1,2].
Regulation through nuclear receptors and
transcription factors
Among other mechanisms, PUFAs have been shown
to exert their effects on gene transcription via nuclear
receptors such as peroxisome proliferator-activated
receptors (PPARs) and liver X receptors (LXRs), and
through the transcription factor, sterol regulatory
element binding protein (SREBP).
Nuclear receptors are found only in metazoan
organisms and consist of two domains: the ligand
binding domain and the DNA binding domain.
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Harini Sampath and James M. Ntambi
Binding of a ligand causes the receptor to bind to a
nuclear receptor response element on target genes
(Figure 1) and regulate transcription of the target gene
[13].
PPARs are a family of nuclear receptors consisting of
three isoforms: PPARa, PPARb/d, and PPARg. PPARa
is strongly activated by the fibrate class of drugs used
in the management of high plasma cholesterol,
whereas PPARg is a target of the thiazolidinediones
used in the clinical management of diabetes and
insulin resistance [14]. In general, both n-3 and n-6
PUFAs have been shown to function via PPARa
to upregulate transcription of genes involved in
b-oxidation, such as carnitine palmitoyl transferase-1
(CPT-1), acyl CoA oxidase and CYP4A2 [1,15].
Another set of nuclear receptors shown to mediate
the hypolipidemic effects of PUFAs are the liver X
receptors. LXRs a and b bind oxysterols as endogenous ligands and function to regulate genes involved
in fatty acid and cholesterol metabolism [16],
including SREBP-1c, lipoprotein lipase, fatty acid
synthase (FAS), acetyl CoA carboxylase (ACC), and
stearyl CoA desaturase-1 (SCD1). LXRs also regulate
genes involved in bile acid synthesis, such as 7-a
hydroxylase [17]. Studies in established cell lines
have suggested that PUFAs may inhibit the hyperlipidemic effects of LXRs in a variety of ways [18,19].
However, there is also evidence that, although the
administration of PUFA in vivo does decrease the
expression of lipogenic genes, this is not accompanied
by changes in classical LXRa target genes [20]. Thus
further research is needed to clarify whether PUFAs
have a role in modulating LXRa activity in vivo [21].
One of the best-characterized modes of regulation
of gene expression by PUFAs is through the lipogenic
transcription factor, SREBP. SREBP-1c is the predominant SREBP isoform in human and rodent liver,
and regulates genes of fatty acid and triglyceride
synthesis [22]. PUFAs have been shown to inhibit
expression of the SREBP-1c gene [23] and proteolytic
maturation [24], resulting in decreased transcription
of SREBP-1c target genes such as ACC, FAS, glycerol
phosphate acyl transferase, SCD1, and SREBP-1 itself.
Conclusion
Research undertaken over the past few decades has
certainly made it clear that fat is more than just an
inert storage form of energy. Even in the face of the
growing obesity epidemic that brings with it a host of
secondary lipid-related conditions, there is growing
understanding, not only that is fat an essential
nutrient, but also that the type and amount of fat
ingested can have dramatic effects on health. At the
same time, there is some controversy regarding the
use of n-3 PUFAs to improve health. The findings of a
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recent meta-analysis suggested that n-3 fatty acids
may offer no added protection against cardiovascular
disease or cancer as previously believed [25]. Rather,
the risk of exposure to toxic chemicals such as methylmercury dioxins and polychlorinated biphenyls,
which are also concentrated in fatty fish high in n-3
fatty acids, may negate any beneficial effects of
n-3 PUFAs [25]. The emergence of such conflicting
reports on the possible effects of an essential nutrient
makes further research on the topic all the more essential. Understanding the site-specific molecular effects
of particular fatty acids will no doubt be key both to
establishing valid dietary recommendations and to
formulating new approaches to combat growing
medical issues.
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